Molecular Approaches to Drug Abuse Research Volume III: Recent Advances and Emerging Strategies
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Molecular Approaches to Drug Abuse Research Volume III: Recent Advances and Emerging Strategies Editor: Theresa N.H. Lee, Ph.D. NIDA Research Monograph 161 1996 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute on Drug Abuse Division of Basic Research 5600 Fishers Lane Rockville, MD 20857 ACKNOWLEDGMENT This monograph is based on the papers from a technical review on "Molecular Approaches to Drug Abuse Research" held on March 22-23, 1994. The review meeting was sponsored by the National Institute on Drug Abuse. COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder's permission is required. All other material in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without permission from the Institute or the authors. Citation of the source is appreciated. Opinions expressed in this volume are those of the authors and do not necessarily reflect the opinions or official policy of the National Institute on Drug Abuse or any other part of the U.S. Department of Health and Human Services. The U.S. Government does not endorse or favor any specific commercial product or company. Trade, proprietary, or company names appearing in this publication are used only because they are considered essential in the context of the studies reported herein. National Institute on Drug Abuse NIH Publication No. 96-4022 Printed 1996 NIDA Research Monographs are indexed in the Index Medicus. They are selectively included in the coverage of American Statistics Index, BioSciences Information Service, Chemical Abstracts, Current Contents, Psychological Abstracts, and Psychopharmacology Abstracts. ii Table of Contents Click on page or subject to go to page Introduction . 1 Theresa N.H. Lee Immunological Approaches to Nicotine Receptors . 3 James W. Patrick, Shawn Neff, Kelly Dineley, and David Char The Dopamine D4 Receptor . 20 Hubert H.M. Van Tol Behavioral Characterization of Mice Packing the 5-HT1B Receptor . 39 Sylvie Ramboz, Frédéric Saudou, Djamel Aït Amara, Catherine Belzung, Andrée Dierich, Marianne LeMeur, Louis Segu, René Misslin, Marie-Christine Buhot, and René Hen Mechanisms Regulating Proenkephalin Gene Expression: Contributions of Transgenic Models . 59 Steven E. Hyman and David Borsook Human Opioid Receptors: Chromosomal Mapping and mRNA Localization . 72 Karen Miotto, Daniel Kaufman, Benito Anton, Duane E. Keith, Jr., and Chris J. Evans Molecular Biology of Opioid Receptors . 83 Karen Raynor, Haeyoung Kong, Susan Law, Jennifer Heerding, Melanie Tallent, Fredrick Livingston, John Hines, and Terry Reisine Mu Opioid Receptors: Cellular Action and Tolerance Development . 104 Anton Mestek, Yan Chen, and Lei Yu Cloning and Characterization of Multiple Opioid Receptors . 127 Huda Akil, Fan Meng, Alfred Mansour, Robert Thompson, Guo-Xi Xie, and Stanley Watson iii Regulation of Acute and Chronic Opioid Receptor Functions by OBCAM, a Cell Adhesion-Like Molecule . 141 Horace H. Loh and Andrew P. Smith Discrete Structural Domains and Cell-Specific Expression Determine Functional Selectivity of the Dopamine and Norepinephrine Transporters . 154 Kari J. Buck, Dominique Lorang, and Susan G. Amara Drug Interactions with Vesicular Amine Transport . 176 Doris Peter, Juan Jimenez, Yongjian Liu, Andrew Merickel, David Krantz, and Robert H. Edwards Strategies for Identifying Genes Underlying Drug Abuse Susceptibility . 201 John C. Crabbe, Kari J. Buck, Pamela Metten, and John K. Belknap iv Introduction: Molecular Approaches to Drug Abuse Research Theresa N.H. Lee The Extramural Molecular Biology and Genetics Program was launched in 1988 in the Division of Basic Research of the National Institute on Drug Abuse (NIDA) to encourage and support investigator-initiated basic research to employ molecular approaches to drug abuse research on all abused substances. In the past 6 years, the program has reached many milestones and achieved numerous successes. The progress made prior to 1991 was best documented in NIDA Research Monograph Series volumes 111 and 126 based on the proceedings of the first and second conferences on "Molecular Approaches to Drug Abuse Research" held in 1989 and 1991, respectively. The third conference on "Molecular Approaches to Drug Abuse Research" was held on March 22 and 23, 1994, at the Bethesda, MD, campus of the National Institutes of Health. This conference intended to capture the recent major advances in this field and to look at the future directions of the program. The Molecular Biology and Genetics Program has indeed come a long way since 1988. NIDA not only has persuaded an unprecedented number of outstanding scientists to join the extramural scientific community engaging in drug abuse research, but recently celebrated the molecular cloning of the opioid receptors that had eluded numerous dedicated drug abuse researchers for more than 15 years. With the completion of the tedious task of gene cloning of all the pertinent receptors, transporters, channels, and regulatory proteins, a new era has begun. Using these powerful tools, researchers can now employ approaches previously unimaginable and concentrate their efforts and resources on elucidating the basic mechanism of each abused substance as well as the molecular and cellular mechanisms underlying tolerance, dependence, and withdrawal to generate better strategies for effective treatment, education, and prevention. This conference was organized into three technical sessions: transgenic/ knockout animal models and other genetic approaches, studies on three families of transporters, and a whole session devoted to the rapidly progressing field of opioid receptors. Thirteen accomplished scientists presented their cutting-edge research, which 1 included many of the major breakthroughs in the field. Due to the ceiling on the number of speakers to invite for the conference, only one example from each category or superfamily could be included rather than encompassing all the recent accomplishments. The proceedings of this conference are presented in the following chapters of this monograph. By the time this monograph is published, virtually all the speakers at this conference will be members of the NIDA extramural scientific community. Under the able leadership of Dr. James Patrick, significant consensus among the speakers has also been reached during the discussion session of this conference. Some of the highlights are: (1) refining tools for producing transgenic/knockout animals, especially conditional or tissue-specific knockouts; (2) developing effective expression systems for drug receptors; (3) expanding research on the polymorphism and diversity of drug receptors, transporters, and other relevant proteins; (4) developing clinically useful, safe opioid drugs employing the knowledge obtained from recent opioid receptor advances; and (5) using proper animal models to systematically screen nongenetic factors for clues leading to treatment of addiction. AUTHOR Theresa N.H. Lee, Ph.D. Program Director Molecular Biology and Genetics Program Division of Basic Research National Institute on Drug Abuse Parklawn Building, Room 10A-19 5600 Fishers Lane Rockville, MD 20857 2 Immunological Approaches to Nicotine Receptors James W. Patrick, Shawn Neff, Kelly Dineley, and David Char Nicotine is a drug whose abuse results in approximately 400,000 deaths per year in the United States alone (Surgeon General 1988). It is by many accounts the most addictive drug available without prescription; nearly 40 percent of those currently addicted have tried to stop using the drug (Schellingt 1992). Although many are successful in overcoming their dependence, 80 percent of those who stop using return to the drug within 24 months (Schellingt 1992). New drug replacement protocols are increasing the success rate, but pharmacokinetic problems of dosage, route, and side effects remain. Clearly, new drugs and new protocols that would help overcome addiction to nicotine would be valuable and might reduce the loss of life that results from its use. Drugs of abuse such as nicotine exert both short-term and long-term effects through their interactions with specific molecular targets such as receptors, ion channels, and transporters. A powerful approach to the study of these drugs has been the identification and study of their specific binding sites and mechanisms of action. This approach has the straight-forward and valid rationale that if one understands the mechanism of action of a drug one can eventually understand and reduce its potential for abuse. In addition, if one understands the binding site one can perhaps design drugs with great receptor specificity and lower abuse potential, which could be used to break dependence. Early biochemical data supported this idea that the sites of action of drugs were homogeneous. However, the idea of a single class of sites for each drug essentially precluded the idea of designing ligands that might distin-guish between binding sites associated with abuse and binding sites for the same drug that might not be associated with abuse. Although the apparent homogeneity of binding sites seemingly facilitated biochemical and binding studies, it moved the authors’ explanations of drug action